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Abstract
Cancer, next only to heart diseases, is the second leading cause of deaths in the United States of
America and many other nations in the world. The prognosis for a patient with metastatic
carcinoma of the lung, colon, breast, or prostate (four of the most common and lethal forms of
cancer, which together account for more than half of all deaths from cancer in the USA), remains
dismal. Conventional therapeutic and surgical approaches have not been able to control the
incidence of most of the cancer types. Therefore, there is an urgent need to develop mechanism-
based approaches for the management of cancer. Chemoprevention via non-toxic agents could be
one such approach. Many naturally occurring agents have shown cancer chemopreventive
potential in a variety of bioassay systems and animal models, having relevance to human disease.
It is appreciated that an effective and acceptable chemopreventive agent should have certain
properties: (a), little or no toxic effects in normal and healthy cells; (b), high efficacy against
multiple sites; ©capability of oral consumption; (d), known mechanism of action; (e), low cost;
and (f), acceptance by human population. Resveratrol is one such agent. A naturally occurring
polyphenolic antioxidant compound present in grapes, berries, peanuts and red wine. In some
bioassay systems resveratrol has been shown to afford protection against several cancer types.
The mechanisms of resveratrol's broad cancer chemopreventive effects are not completely
understood. In this review, we present the cancer chemopreventive effects of resveratrol in an
organ-specific manner. The mechanisms of the antiproliferative/ cancer chemopreventive effects
of resveratrol are also presented. We believe that continued efforts are needed, especially well-
designed pre-clinical studies in the animal models that closely mimic/represent human disease, to
establish the usefulness of resveratrol as cancer chemopreventive agent. This should be followed
by human clinical trials in appropriate cancer types in suitable populations.
Key words: Resveratrol , Cancer, Chemoprevention

Introduction
Cancer , next only to heart diseases , is the second
leading cause of deaths in the United States of
America and many other nations in the world .
Despite immense efforts to improve treatment
and find cures for it , overall mortality rates have
not significantly reduced in the past 25 years .
The prognosis for a patient with metastatic
carcinoma of the lung , colon , breast or prostrate
is dismal . Conventional medicine treats cancer
along the lines of an infection . This has lead to
radical attempts to get rid of the disease through
the ‘cut , burn and poison’ technique of surgery ,
radiation and chemotherapy . This approach has
not been successful in cancer management and
has been criticized . When pre-cancerous cells are
formed in the body the immune system detects
and destroys them before it becomes a problem .
If the immune system is weak , cancer appears .
The answer to combat cancer lies in prevention
rather than cure .
Chemoprevention via non-toxic agents could be
such an approach . Chemoprevention is defined
as the use of pharmacological and natural agents
to prevent , arrest or reverse the process of cancer
development before invasion and metastasis
occur . Dietary factors contribute to one-third of
potentially preventable cancers . Many naturally
occurring agents have shown cancer chemo
preventive potential in a variety of bioassay
systems and animal models , having relevance to
human disease . It is appreciated that an effective
and acceptable chemopreventive agent should
have some properties : (a) little or no toxic effects
in normal and healthy cells (b) high efficacy
against multiple sites © capability of oral
consumption (d) known mechanism of action (e)
low cost (f) acceptance by human population .
Resveratrol is one such agent , which has been
shown to possess many biological activities
relevant to human diseases . Resveratrol ,
chemically known as 3,5,4'-trihydroxy-stilbene ,
is a naturally occurring polyphenolic anti-oxidant
compound present in grapes , berries , peanuts
and red wine. Some epidemiological studies
have indicated that red wine protects against
many diseases including cancer . ( The traditional
Japanese and Chinese folk medicines have used
root extract of the weed Polygonum cupsidatum
which has resveratrol to fight liver , skin and
circulatory diseases . Resveratrol possesses
cancer chemopreventive effects against all the
three major stages of carcinogenesis i.e. initiation
, promotion and progression .
Cancer
What is Cancer ?
Cancer (medical term: malignant neoplasm) is a
class of diseases in which a group of cells
display uncontrolled growth (division beyond
the normal limits) , invasion (intrusion on and
destruction of adjacent tissues ) , and sometimes
metastasis (spread to other locations in the body
via lymph or blood) . These three malignant
properties of cancers differentiate them from
benign tumors , which are self-limited, and do
not invade or metastasize. Most cancers form a
tumor but some , like leukemia , do not. The
branch of medicine concerned with the study ,
diagnosis , treatment , and prevention of cancer
is oncology.
Cancer affects people at all ages with the risk for
most types increasing with age . Cancer caused
about 13% of all human deaths in 2007 .
Cancers are caused by abnormalities in the
genetic material of the transformed cells . These
abnormalities may be due to the effects of
carcinogens such as tobacco smoke , radiation ,
chemicals , or infectious agents . Other cancer-
promoting genetic abnormalities may randomly
occur through errors in DNA replication , or are
inherited , and thus present in all cells from birth.
The heritability of cancers is usually affected by
complex interactions between carcinogens and
the host's genome .
Genetic abnormalities found in cancer typically
affect two general classes of genes . Cancer-
promoting oncogenes are typically activated in
cancer cells , giving those cells new properties ,
such as hyperactive growth and division ,
protection against programmed cell death , loss
of respect for normal tissue boundaries , and the
ability to become established in diverse tissue
environments.
Classification
Cancers are classified by the type of cell that
resembles the tumor and , therefore, the tissue
presumed to be the origin of the tumor. These are
the histology and the location , respectively.
Examples of general categories include :
• Carcinoma: Malignant tumors derived
from epithelial cells. This group
represents the most common cancers, including the common forms of breast,
prostate, lung and colon cancer.
• Sarcoma: Malignant tumors derived
from connective tissue, or
mesenchymal cells.
• Malignancies derived from
hematopoietic (blood-forming) cells
• Germ cell tumor : Tumors derived from
totipotent cells. In adults most often
found in the testicle and ovary ; in
fetuses , babies , and young children
most often found on the body midline ,
particularly at the tip of the tailbone ; in
horses most often found at the poll (base
of the skull).
• Blastic tumor or blastoma: A tumor
(usually malignant) which resembles an
immature or embryonic tissue. Many of
these tumors are most common in
children .
Signs And Symptoms
Symptoms of cancer metastasis depend on the
location of the tumor. Roughly , cancer
symptoms can be divided into three
groups:
• Local symptoms: unusual lumps
or swelling (tumor) ,
hemorrhage (bleeding) , pain
and/or ulceration .
Compression of surrounding
tissues may cause symptoms
such as jaundice (yellowing
the eyes and skin) .
• Symptoms of metastasis
(spreading): enlarged lymph
nodes , cough and
hemoptysis , hepatomegaly
(enlarged liver), bone pain ,
fracture of affected bones and
neurological symptoms.
Although advanced cancer may
cause pain , it is often not the
first symptom.
• Systemic symptoms: weight
loss , poor appetite, fatigue
and cachexia (wasting) ,
excessive sweating (night
sweats) , anemia and specific
paraneoplastic phenomena,
i.e. specific conditions that are
due to an active cancer , such as
thrombosis or hormonal
changes .
Causes
• A mutation in the error-correcting
machinery of a cell might cause that cell
and its children to accumulate errors
more rapidly .
• A mutation in signaling (endocrine)
machinery of the cell can send error-
causing signals to nearby cells .
• A mutation might cause cells to become
neoplastic , causing them to migrate
and disrupt more healthy cells .
• A mutation may cause the cell to
become immortal (see telomeres) ,
causing them to disrupt healthy cells
forever .
What Is Resveratrol ?
Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is a
phytoalexin produced naturally by several plants
when under attack by pathogens such as bacteria
or fungi as a defence against diseases.
Resveratrol is a flavonol belonging to the group
of flavonoids. It is a naturally occuring
polyphenolic antioxidant compound in grapes ,
berries , peanuts and red wine . Resveratrol is
found in the skin of red grapes and is a
constituent of red wine . Resveratrol has also
been produced by chemical synthesis and is sold
as a nutritional supplement derived primarily
from Japanese knotweed .
Resveratrol was first mentioned in a Japanese
article in 1939 by M . Takaoka , who isolated it
from the poisonous but medicinal Veratrum
album , variety grandiflorum .
Chemical Structure Of Resveratrol
The chemical structure is important because
from its structure information regarding the
biological activity may be obtained . Because it
has more than one phenol groups this is
classified as a polyphenol . Polyphenols are
antioxidants as they react with free radicals to
form a stable molecule that is less toxic than the
original compound
gents to reverse, suppress, or prevent
carcinogenic progression to invasive cancer.
Chemoprevention is also called
chemoprophylaxis . It is the use of natural or
laboratory-made substances to prevent a disease
such as cancer. The regular use of aspirin is
known to reduce the risk of the polyps from
which colorectal cancer arises. This is an
instance of chemoprevention.
The term chemoprevention was coined
to parallel the term chemotherapy .
Chemoprevention prevents and
chemotherapy treats .
Chemoprevention By Resveratrol
Resveratrol acts as an antioxidant and
antimutagen . It induces phase II drug
metabolising enzymes (anti –initiation activity ) .
It inhibits cyclooxygenase and hydroperoxidase
functions (anti-promotion activity). It mediates
anti-inflammatory effects. It induces human
promyelocytic leukemia cell differentiation (anti
-progression activity) . In addition it has
inhibited development of preneoplastic lesions in
carcinogen treated mouse mammary glands in
culture and inhibited tumorigenesis in a mouse
skin cancer model .
It has shown to impart anti-proliferative effects
on human breast epithelial cells . Resveratrol
induced significant dose-dependent inhibition in
human oral squamous carcinoma cell (SCC-25)
growth and DNA synthesis. Resveratrol reduced
viability and DNA synthesis capability of human
promyelocytic leukemia (HL-60) cells, via an
induction of apoptosis through BCl-2 pathway .
Resveratrol has also been shown to regulate PSA
gene expression by an AR-independent
mechanism . Many antioxidant polyphenols
present in wine including resveratrol inhibit the
proliferation of human prostate cancer cell lines .
Resveratrol has shown strong anti-proliferative
properties that has been attributed to its ability to
efficiently scavenge the essential tyrosyl radical
of the small protein of ribonucleotide reductase
and, consequently, to inhibit deoxyribonucleotide
synthesis. It was also observed that resveratrol
non-competitively inhibited the cyclooxygenase
(COX)-2 transcription and activity in human
mammary epithelial cells and colon cancer cells .
Resveratrol was found to act as a potential
inhibitor of inducible NO synthase (iNOS) and
inducible COX-2 . Resveratrol also demonstrated
anti-inflammatory effects and inhibited the
activity of hydroperoxidase enzymes (suggestive
of anti- promotion activity) in addition to cause
the differentiation of human promyelocytic
leukemia cells, indicating that this compound
may also depress the progression phase of
cancer .
Several studies have shown that the cancer
preventive activity of resveratrol could be
attributed to its ability to trigger apoptosis in
carcinoma cells . Few researchers have shown
that resveratrol is metabolized by the enzyme
cytochrome P450 (CYP)-1B1, which is found in
a variety of different tumors. When resveratrol is
metabolized by the CYP1B1, an anti-leukemic
agent piceatannol is formed that has been
previously identified as an anti- leukemic agent.
This observation provides a novel explanation for
the cancer preventive properties of resveratrol
.These studies suggested that resveratrol may be
developed as a potential cancer chemopreventive
agent .
Resveratrol And Cancer
Many studies in cell culture system as well as in
animal models have shown the cancer
chemopreventive as well as cancer therapeutic
effects of resveratrol . The organ specific cancer
chemo-preventive effects of this polyphenol i.e.
antioxidant that may be a constituent of diet
and/or beverages consumed by human population
has been summarized .
Resveratrol And Skin Cancer
In the USA, non-melanoma skin cancer that
includes basal and squamous-cell carcinoma, is
the most frequently diagnosed form of cancer
accounting for nearly half of all cancer types .
According to an estimate, more than a million
new cases of skin cancer are diagonised annually
in the USA . Depending on the cellular origin ,
human skin cancer is classified as melanocytic or
epithelial ; melanomas are less common but more
lethal than epithelial skin cancers . Studies have
shown that resveratrol prevents the development
of skin cancer. In fact, the first study showing the
cancer chemopreventive effect of resveratrol
demonstrated that resveratrol acts as an effective
agent for the prevention of chemically-induced
skin carcinogenesis . The application of TPA to
mouse skin induces oxidative stress as evidenced
by several biochemical responses including
generation of and enhanced levels of
myeloperoxidase and oxidized glutathione
reductase activities and decreases in glutathione
levels and superoxide dismutase activity . TPA
treatment was also found to elevate the
expression of cyclooxygenase-1 (COX-1) , COX-
2 , c-myc, c-fos , c-jun, transforming growth
factor-ß1 (TGF-ß1) and tumor necrosis factor
(TNF) . The pre-treatment of mouse skin with
resveratrol negated several of these TPA-induced
effects in a dose-dependent manner . and
glutathione reductase and superoxide dismutase
activities . The reverse transcriptase . polymerase
chain reaction (RT-PCR) analysis showed that
TPA-induction increases the expression of c-fos
and the TGF-ß1 were inhibited by resveratrol . In
addition resveratrol inhibited the de novo
formation of inducible nitric oxide synthase
(Inos) in mouse macrophages stimulated with
lipopolysaccharide .It was showed that in a
mouse JB6epidermal cell line , resveratrol
activated extracellular-signal-regulated protein
kinases (ERKs) , c-Jun NH -terminal kinases
(JNKs), and p38 kinase and induced serine 15
phosphorylation of p53 . Pretreatment of the cells
with PD98059 or SB202190 or stable expression
of a dominant negative mutant of ERK2 or p38
kinase impaired resveratrol-induced p53-
dependent transcriptional activity and apoptosis ,
whereas constitutively active MEK1 increased
the transcriptional activity of p53 . These data
strongly suggest that both ERKs and p38 kinase
mediate resveratrol-induced activation of p53 and
apoptosis through phosphorylation of p53 at
serine 15 .
It was determined that c-jun NH(2) terminal
kinases (JNKs) are involved in resveratrol-
induced p53 activation and induction of apoptosis
in JB6 mouse epidermal cells. Resveratrol
activated JNKs dose-dependently . The data
suggested that JNKs act as mediators of
resveratrol-induced activation of p53 and
apoptosis, which may occur partially through p53
phosphorylation .
Chemopreventive potential of stilbenes (trans-
resveratrol is reported to be most effective among
several red wine polyphenols viz. flavanols [(+)-
catechin], flavonols (quercetin) and
hydroxybenzoic acids (gallic acid) . It was
concluded that trans-resveratrol may be the most
effective anticancer polyphenol present in red
wine .
In another study, chemopreventive capability of
reseveratrol was found to be most effective
compared to sesamol, sesame oil and sunflower
oil .
It was suggested that non-melanoma skin cancer
is related to cumulative exposure to solar
ultraviolet radiation.
Resveratrol treatment of keratinocytes was also
found to inhibit UVB mediated: (i),
phosphorylation and degradation of I B (ii)
activation of IKK . Based on the data,we
suggested that NF- B pathway plays a critical role
in the chemopreventive effects of resveratrol
against the adverse effects of UV radiation
including photocarcinogenesis .
Resveratrol And Liver Cancer
Few studies have evaluated the chemopreventive
effects of resveratrol against liver cancer. It was
demonstrated that resveratrol administration to
rats inoculated with a fast growing tumour (the
Yoshida AH-130 ascites hepatoma) caused a very
significant decrease (25%) in the tumor cell
content. This effect was found to be associated
with an increase in the number of cells in the
G2\M phase of the cell cycle . Resveratrol causes
apoptosis in the tumor cell. Resveratrol inhibited
the growth of hepatoma cells line H22 in a dose-
and time-dependent manner via the induction
of apoptosis .
Resveratrol suppressed the invasion of the
hepatoma cells even at low concentrations .
Resveratrol and resveratrol-loaded rat serum
suppressed reactive oxygen species-mediated
invasive capacity. It was strongly found to inhibit
cell proliferation .
Resveratrol inhibits CYP1A1 expression in
vitro , by preventing the binding of the AHR to
promoter sequences that regulate CYP1A1
transcription . This was suggested to be important
for chemopreventive activity of resveratrol .
Resveratrol inhibits aryl hydrocarbon induced
CYP1A activity in vitro inhibiting
CYP1A1\CYP1A2 enzyme activity and by
inhibiting the signal transduction pathway that
upregulates the expression of carcinogen
activating enzymes.
Resveratrol and lung cancer
The chemopreventive activities of butylated
hydroxyanisole (BHA) , myo-inositol ,
curcumin , esculetin, resveratrol and lycopene-
enriched tomato oleoresin (LTO) against lung
tumor induction in A/J mice by the tobacco
smoke carcinogens benzo[a]pyrene (BaP) and
4-(methyl-nitrosamino)-1-(3- pyridyl)-1-butanone
(NNK) were evaluated . In this study, the mice
treated with BHA and NNK had reduced lung
tumor multiplicity .
The effects of stilbene glucosides isolated from
medicinal plants and grapes on tumor growth and
lung metastasis in mice bearing highly metastatic
Lewis lung carcinoma (LLC) tumors were
studied . Stilbene glucosides are naturally
occurring phytoalexins , found in a variety of
medicinal plants . Among the stilbene derivatives
resveratrol 3-O-D-glucoside is found in grapes
and wine .Tumor growth in the right hind paw
and lung metastasis were inhibited by oral
administration of resveratrol 3-O-D-glucoside
and 2,3,5,4'-tetrahydroxystilbene-2-O-D-
glucoside for 33 consecutive days , in LLC-
bearing mice. In addition, both stilbene
glucosides inhibited angiogenesis of HUVECs ,
The authors of this study suggested that the
antitumour and antimetastatic activity of
resveratrol 3-O-D-glucoside and 2,3,5,4'-
tetrahydroxystilbene-2-O-D- glucoside, might be
due to the inhibition of DNA synthesis in LLC
Resveratrol and blood cancer
The anti-proliferative/ chemopreventive effects of
resveratrol against leukemia were evaluated .
Resveratrol reduced the viability and DNA
synthesis capability of cultured human
promyelocytic leukemia (HL-60) cells . In this
study the growth inhibitory and antiproliferative
properties of resveratrol were suggested to be
attributable to its induction of apoptotic cell death
as determined by morphological and
ultrastructural changes , internucleosomal DNA
fragmentation and increased proportion of the
sub-diploid cell population .Further, resveratrol
treatment resulted in a gradual decrease in the
expression of anti-apoptotic Bcl-2 . Involvement
of caspases and CD95-CD95 ligand pathway in
resveratrol-mediated induction of apoptosis in the
myeloid leukemia HL60 cells . Resveratrol-
treated tumor cells exhibited a dose-dependent
increase externalization of inner membrane
phosphatidylserine and in cellular content of
subdiploid DNA , indicating loss of membrane
phospholipid asymmetry and DNA fragmentation Resveratrol-induced cell death was found to be
mediated by intracellular caspases as observed by
the dose-dependent increase in proteolytic
cleavage of caspase substrate poly (ADP-ribose)
polymerase (PARP) and the ability of caspase
inhibitors to block resveratrol cytotoxicity . These
data showed specific involvement of the CD95-
CD95L system in the anti-cancer activity of
resveratrol and highlight the chemotherapeutic
potential of this natural product , in addition to its
recently reported chemopreventive activity .
Another study has shown that resveratrol
induces Fas signaling-independent apoptosis in
THP-1 human monocytic leukaemia cells (125).
Bernhard demonstrated that resveratrol induced
arrest in the S phase and apoptosis .
Resveratrol induced extensive apoptotic cell
death not only in CD95-sensitive leukemia lines ,
but also in B-lineage leukemic cells that are
resistant to CD95-signaling .
Some studies revealed the proapoptotic potential
of resveratrol and its hydroxylated analog
piceatannol . These agents are potent inducers of
apoptotic cell death in Burkitt-like lymphoma
cells . Resveratrol imparts anti-leukemic activity
against mouse and human leukemic cell lines by
inhibiting proliferation . Inhibition of leukemic
cell lines by resveratrol was due to induction of
apoptosis .
The french paradox
Despite the heavy consumption of cheese, butter ,
eggs, rich creamy sauces , and other fat-
containing foods , the French population appears
to be surprisingly healthy, with low incidence of
coronary heart diseases and certain types of
cancer. Although a typical French diet contains
approximately 15% more saturated fat than an
American diet , and even though they exercise
less than Americans , the rate of heart diseases for
the French people is 60% lower than that of
Americans . Similarly , the incidence of certain
cancer types are much lower in French population
than in American . This has been attributed to
high consumption of red wine by French people
that in fact ranks to the highest per capita
consumption in the world . This phenomenon has
been dubbed as the French Paradox .
Conclusion
A structured path for developing diet derived
agents as cancer chemopreventive is emerging
fast . Resveratrol , a polyphenolic compound
present in grapes , red wine , nuts and berries has
shown promise against certain cancer types like
liver , lung , prostate , blood , skin , colorectal
and intestinal cancers . In various in vitro and in
vivo models, resveratrol has proved to be capable
of retarding steps of carcinogenesis . The
compound also bears a simple chemical structure
that is capable of interacting with a variety of
receptors and enzymes and serving as an
activator or inhibitor in a number of pathways
No toxicity reports have been published with
respect to resveratrol in animals. Resveratrol has
proven to be non-toxic , even at high doses
(3,000mg/kg diet for 120 days in rats) . Since
resveratrol is an active ingredient of several
traditional medicines used for centuries in India,
China, and Japan, the general medicinal value
and safety of this compound may be suggested .
.
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